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==Gene Overview==

==Gene Overview==

''TP53'', encoding p53, is an oncogene, tumor suppressor, and regulator of DNA repair. Inactivating ''TP53'' mutations are common in human tumors and they are a hallmark of a hereditary cancer predisposition disorder known as Li-Fraumeni syndrome [1-4].

''TP53'', encoding p53, is an oncogene, tumor suppressor, and regulator of DNA repair. ''TP53'' has been implicated in many cancer types, is classically considered the prototypic tumor suppressor gene, and inactivating ''TP53'' mutations are also a hallmark of a hereditary cancer predisposition disorder known as Li-Fraumeni syndrome [1-4,16-17].

''Mutational spectrum'' - Approximately half of all cancers harbor a ''TP53'' mutation, though the frequency and the distribution of mutations can vary between tumor types.  See Figure 2 in [5]. The most common ''TP53'' mutations are missense mutations in the DNA-binding domain. Most of the ''TP53'' single-nucleotide variants (SNVs) are missense mutations (25% of these mutations are five ‘hotspot’ mutations) [5]. Approximately 25% of ''TP53'' mutations are nonsense or frameshift mutations; the remainders are splice site SNVs and in-frame indels of unclear biological significance [5]. Biallelic loss of ''TP53'' commonly occurs via segmental deletion; the deletions vary widely in size and occur at a frequency similar to ''TP53'' SNVs. About 25% of tumors harbor the canonical ''TP53'' missense mutation/deletion combination, but all other potential variant combinations leading to biallelic loss of function are seen [5,9].

''Mutational spectrum'' - Approximately half of all cancers harbor a ''TP53'' mutation, though the frequency and the distribution of mutations can vary between tumor types.  See Figure 2 in [5]. The most common ''TP53'' mutations are missense mutations in the DNA-binding domain. Most of the ''TP53'' single-nucleotide variants (SNVs) are missense mutations (25% of these mutations are five ‘hotspot’ mutations) [5]. Approximately 25% of ''TP53'' mutations are nonsense or frameshift mutations; the remainders are splice site SNVs and in-frame indels of unclear biological significance [5]. Biallelic loss of ''TP53'' commonly occurs via segmental deletion; the deletions vary widely in size and occur at a frequency similar to ''TP53'' SNVs. About 25% of tumors harbor the canonical ''TP53'' missense mutation/deletion combination, but all other potential variant combinations leading to biallelic loss of function are seen [5,9]. In some cancers, ''TP53'' mutations co-occur with activating ''KRAS'' mutations or ''MYC'' amplification, demonstrating the cooperation of ''TP53'' with oncogenes to transform primary cells. Genomic copy number variation (a marker of genetic instability) is higher in patients with germline ''TP53'' mutations than in healthy subjects [5,10,11].

In some cancers, ''TP53'' mutations co-occur with activating ''KRAS'' mutations or ''MYC'' amplification, demonstrating the cooperation of ''TP53'' with oncogenes to transform primary cells. Genomic copy number variation (a marker of genetic instability) is higher in patients with germline ''TP53'' mutations than in healthy subjects [5,10,11].

The ''TP53'' gene contains homozygous mutations in about 50-60% of human cancers. About 90% of the mutations in ''TP53'' encode missense mutant proteins that span about 190 codons in the DNA-binding domain; none of the 50 most common pathogenic missense mutations occur outside of the DNA-binding region. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates p53 transcriptional pathway [15]. The eight most common mutations across all cancer types (R175H, R248Q, R273H, R248W, R273C, R282W, G245S, R249S) are found in codons that account for about 28% of the total p53 mutations (See Table 1 in [15]); these alleles appear to be selected for preferentially in human cancers of many tissue types. Seven of the eight mutations occur at methylated CpG sites in ''TP53'', which encode arginine residues that contact the DNA and are conserved over evolutionary time scales [15].

The ''TP53'' gene contains homozygous mutations in about 50-60% of human cancers. About 90% of the mutations in ''TP53'' encode missense mutant proteins that span about 190 codons in the DNA-binding domain; none of the 50 most common pathogenic missense mutations occur outside of the DNA-binding region. These mutations produce a protein with a reduced capacity to bind to a specific DNA sequence that regulates p53 transcriptional pathway [15]. The eight most common mutations across all cancer types (R175H, R248Q, R273H, R248W, R273C, R282W, G245S, R249S) are found in codons that account for about 28% of the total p53 mutations (See Table 1 in [15]); these alleles appear to be selected for preferentially in human cancers of many tissue types. Seven of the eight mutations occur at methylated CpG sites in ''TP53'', which encode arginine residues that contact the DNA and are conserved over evolutionary time scales [15].

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15. Baugh EH, et al., (2018). Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25(1):154-160, PMID 29099487.  

15. Baugh EH, et al., (2018). Why are there hotspot mutations in the TP53 gene in human cancers? Cell Death Differ 25(1):154-160, PMID 29099487.  

== Notes ==

== Notes ==